Diminished salivary gland output often results in the complaint of xerostomia (dry mouth). Salivary gland hypofunction is caused by a number of disorders or their treatments, including Sjogren's syndrome and radiation therapy for cancers of the head and neck. Dry mouth can cause impaired mastication, difficulty swallowing and ulcerations of the oral mucosa, and may even interfere with speech patterns and sleep.
Due to the diminished saliva, Sjogren's syndrome (SS) patients often experience a proliferation of bacteria resulting in tooth decay. The tongue often loses its protective papilla as well. SS patients are also more prone to oral yeast infections. Chapped lips and cracks at the corner of the mouth are also frequently experienced. Moreover, because of these symptoms, SS patients will often change their eating habits to avoid bulky foods (meats, breads, etc.). As a result, nutritional deficiencies may occur causing further complications.
To date, no satisfactory saliva substitute has yet been developed that has been able to duplicate the desirable properties of naturally occurring saliva. At best, saliva substitutes offer temporary relief. Nothing has so far been developed to reverse or halt the progression of diminished salivary gland production.
The approaches to search for treatments to manage salivary gland dysfunction have focused on four basic approaches. Those are (1) prevention; (2) management of the related clinical problems; (3) saliva substitutes; and (4) stimulation of secretions. These approaches to saliva substitutes have not met with any degree of success. Prevention and management of the related clinical problems only work in early stages. Saliva substitute and secretion stimulation deal with more chronic cases. There remain significant opportunities for development of successful treatments to stimulate secretions.
Stimulation of secretion has focused on three basic approaches, namely topical; systemic secretagogues (agents that will stimulate secretions); and finally, treatment of the underlying inflammatory condition.
The present invention represents a new approach to systemic secretagogues. None are currently available in the United States. Only one has generally been recognized on a world-wide basis as somewhat useful, and that is pilocarpine hydrochloride. Pilocarpine however is known to produce side effects involving the heart, blood pressure, and digestion. Moreover, it does not seem to stimulate the salivary gland to produce more saliva, but simply to release that which the patient has left. In other words, it only stimulates remaining functioning tissues, not increase salivary production as a whole. It can therefore be seen that there is a continuing and real need for the development of a safe and effective means for stimulating salivary function.
It has now been discovered that certain sigma site binding ligands can be administered successfully as a systemic secretagogue which is more effective than pilocarpine and yet does not cause side effects like pilocarpine.
The term "ligand" is used herein to generally describe the tissue binding portion of the active molecules referred to below. Some of these represent molecules which have earlier been found to be lacrimal stimulants, U.S. Pat. No. 4,820,737 and some have been found to be psychoactive sigma cite binding drugs, Schoenwald et al., Ser. No. 557,581, filed Jul. 24, 1990.
Pharmacological, biochemical and behavioral characterization of sigma binding sites is currently the focus of intense, widespread investigation. While the precise nature of sigma binding sites in cells is not quite known, many studies have suggested that it represents the site of action for a number of important drugs. For example, haloperidol, a butyrophenone antipsychotic, exhibits high affinity for sigma binding sites and several psychotominetics, including PCP and benzomorphan-type compounds (pentazocine), also bind at this site. Thus, strong binding sigma agents are indicative of usefulness in the treatment of schizophrenia.
In fact, several sigma compounds have been developed as antipsychotics. It is also believed that strong sigma site binding may also indicate therapeutic targets for epilepsy and brain ischemia.
In sum, the discovery of sigma binding sites has prompted investigation into the functional role of the sites. While the functional role is not precisely understood, it is nevertheless true that binding studies have revealed sigma sites which may exhibit a unique pharmacological profile, and have provided evidence favoring the existence of a multiplicity of sigma binding sites in the central nervous system.
The present invention is predicated upon the discovery that certain sigma ligands can be effective systemic secretagogues, and therefore, used to effectively treat dry mouth.
The primary objective of the present invention is to provide an effective salivary stimulant, which can be topically administered to selectively stimulate secretions in the oral cavity.
Another objective of the present invention is to provide compounds which are as effective, and in most cases, more effective than pilocarpine hydrochloride as systemic secretagogues, but which do not have the adverse side effects of pilocarpine hydrochloride.
Another objective of the present invention is to provide salivary stimulants that do not produce undesirable pharmacological side effects such as copious sweating, excessive salivation, gastric secretion and papillary constriction.
Another object of the present invention is to provide an orally effective salivary stimulant with action limited to the oral cavity, which has a reasonable duration of effect, and produces minimum side effects.
Another object of the present invention is to provide to the art the fundamental knowledge that salivary glands contain sigma receptors, and thus, some sigma site binding ligands are active in salivary stimulation.
The method and manner of accomplishing each of the above objectives as well as others will become apparent from the detailed description of the invention which follows hereinafter.